Dissertation committee:
Δημήτριος Μπούμπας, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Σωτήριος Τσιόδρας, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ιωάννης Καλομενίδης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ουρανία Τσιτσιλώνη, Καθηγήτρια, Βιολογία, ΕΚΠΑ
Κωνσταντίνος Ρίτης, Καθηγητής, Ιατρική Σχολή, Δημοκρίτειο Πανεπιστήμιο Θράκης
Πασχάλης Σιδεράς, Ερευνητής Α', Κλινική, Πειραματική Χειρουργική & Μεταφραστική Έρευνα, ΙΙΒΕΑΑ
Ευδοκία Καραγκούνη, Ερευνήτρια Α', Τμήμα Μικροβιολογίας, Ελληνικό Ινστιτούτο Παστέρ
Summary:
Activins are members of the Transforming Growth Factor β (TGFβ) superfamily and have been associated with the pathogenesis of numerous immuno-inflammatory conditions, having both proinflammatory and anti-inflammatory properties, while also possessing tissue remodeling functions. Understanding the role of Activins in the pathophysiology of the lung needs further research.
Activin-A is found in tissues and circulation in abundance compared to other Activins and its levels have been found strongly deregulated in stressful conditions. Initially, based on the fact that the main cellular source of Activin-A in the early stages of an inflammatory response is neutrophils, we used a transgenic mouse system, in which Activin-A was selectively depleted from this cell population, and the effects induced by Influenza A virus infection were evaluated. We showed that mice with Activin-A deficient neutrophils exhibited more severe pathology compared to wild-type mice and this was largely due to the extensive formation of Neutrophil Extracellular Traps (NETs). This happens to a certain extend through Activin-A signaling via the ALK-4 receptor in neutrophils, since selective elimination of this receptor from neutrophils leads to pathology of influenza-infected mice that is in-between the wild type controls and mice with Activin-A deficient neutrophils. Therefore, it seems that Activin-A that is produced by neutrophils and signals via ALK-4 (on neutrophils but also other as yet not identified inflammatory or tissue resident cells), acts protectively in pathological conditions characterized by neutrophilia as it suppresses processes in this specific cell population, such as NETosis, which potentially cause tissue damage.
Based on previous studies where it was shown that overexpression of Activin-A in the lung causes pathology that mimics the basic features of COVID-19 (Corona Virus Disease 2019) caused by the coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome (COronaVirus 2), we hypothesized that Activins and their natural inhibitor, Follistatin, may be particularly important in the pathophysiology of COVID-19. Therefore, Activin-A, Activin-B, and Follistatin levels were analyzed in 574 serum samples from 263 COVID-19 patients hospitalized in 3 independent centers and compared with baseline demographic, clinical, and laboratory parameters to establish a model for predicting disease status. This study showed that the Activin/Follistatin axis was highly deregulated in patients with COVID-19, was associated with disease severity, and was independently associated with mortality. The FACT-CLINYCoD rating system, which includes Follistatin, Activin-A, Activin-B, C-reactive protein, lactic dehydrogenase, ICU (Intensive Care Unit), neutrophil/lymphocyte ratio, comorbidities and D-dimers have been shown to be particularly effective in predicting death. This study demonstrated a link between the Activin/Follistatin axis and mortality from COVID-19 and introduced FACT-CLINYCoD, a new pathophysiology-based tool that allows dynamic prediction of disease outcome, and could therefore facilitate clinical decision making.
In conclusion, from these two independent but directly related studies, the complex nature of the Activin/Follistatin axis is clearly highlighted. Depending on the disease or the experimental model studied, or as shown for the first time in the current thesis, cellular the source of Activin-A, the A/F axis’ proteins sometimes have a protective and sometimes a harmful effect. These two studies therefore indicate the importance of the dynamic balance in signaling through TGFβ superfamily molecules, and that possibly the selective inactivation (or activation) of A/F axis proteins by specific cell populations may be a better therapeutic strategy than their universal neutralization.
Activins are members of the Transforming Growth Factor β (TGFβ) superfamily and have been associated with the pathogenesis of numerous immuno-inflammatory conditions, having both proinflammatory and anti-inflammatory properties, while also possessing tissue remodeling functions. Understanding the role of Activins in the pathophysiology of the lung needs further research.
Activin-A is found in tissues and circulation in abundance compared to other Activins and its levels have been found strongly deregulated in stressful conditions. Initially, based on the fact that the main cellular source of Activin-A in the early stages of an inflammatory response is neutrophils, we used a transgenic mouse system, in which Activin-A was selectively depleted from this cell population, and the effects induced by Influenza A virus infection were evaluated. We showed that mice with Activin-A deficient neutrophils exhibited more severe pathology compared to wild-type mice and this was largely due to the extensive formation of Neutrophil Extracellular Traps (NETs). This happens to a certain extend through Activin-A signaling via the ALK-4 receptor in neutrophils, since selective elimination of this receptor from neutrophils leads to pathology of influenza-infected mice that is in-between the wild type controls and mice with Activin-A deficient neutrophils. Therefore, it seems that Activin-A that is produced by neutrophils and signals via ALK-4 (on neutrophils but also other as yet not identified inflammatory or tissue resident cells), acts protectively in pathological conditions characterized by neutrophilia as it suppresses processes in this specific cell population, such as NETosis, which potentially cause tissue damage.
Based on previous studies where it was shown that overexpression of Activin-A in the lung causes pathology that mimics the basic features of COVID-19 (Corona Virus Disease 2019) caused by the coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome (COronaVirus 2), we hypothesized that Activins and their natural inhibitor, Follistatin, may be particularly important in the pathophysiology of COVID-19. Therefore, Activin-A, Activin-B, and Follistatin levels were analyzed in 574 serum samples from 263 COVID-19 patients hospitalized in 3 independent centers and compared with baseline demographic, clinical, and laboratory parameters to establish a model for predicting disease status. This study showed that the Activin/Follistatin axis was highly deregulated in patients with COVID-19, was associated with disease severity, and was independently associated with mortality. The FACT-CLINYCoD rating system, which includes Follistatin, Activin-A, Activin-B, C-reactive protein, lactic dehydrogenase, ICU (Intensive Care Unit), neutrophil/lymphocyte ratio, comorbidities and D-dimers have been shown to be particularly effective in predicting death. This study demonstrated a link between the Activin/Follistatin axis and mortality from COVID-19 and introduced FACT-CLINYCoD, a new pathophysiology-based tool that allows dynamic prediction of disease outcome, and could therefore facilitate clinical decision making.
In conclusion, from these two independent but directly related studies, the complex nature of the Activin/Follistatin axis is clearly highlighted. Depending on the disease or the experimental model studied, or as shown for the first time in the current thesis, cellular the source of Activin-A, the A/F axis’ proteins sometimes have a protective and sometimes a harmful effect. These two studies therefore indicate the importance of the dynamic balance in signaling through TGFβ superfamily molecules, and that possibly the selective inactivation (or activation) of A/F axis proteins by specific cell populations may be a better therapeutic strategy than their universal neutralization.
